Ionizing irradiation-induced damage to cells, tissues, and organs involves nuclear DMA strand breaks and associated activation and transport through the cytoplasm to the mitochondria of stress activated protein kinases and other molecules which initiate apoptosis. Oxidative stress events at the mitochondria activate a cascade leading to mitochondrial membrane permeability, cytochrome C leakage, and activation of the caspase pathway for cell death. Mitochondrial permeabilization represents the "point of no return" in the apoptotic pathway. There is no currently available effective, non-toxic, and practical small molecule radiation protector or damage mitigator given before or after the irradiation exposure (respectively). We propose to develop radioprotector/mitigator drugs focused on neutralizing mitochondrial specific steps in early response to irradiation damage which will prevent irreversible cell death. Project 1 focuses on developing mitochondrial targeted superoxide dismutase mimetic molecules which, when added to manganese superoxide dismutase-plasmid/liposome (MnSOD-PL) transgene therapy, limit mitochondrial oxidative damage from ionizing irradiation. Project 2 develops ethyl pyruvate therapy as a stabilization of mitochondrial respiratory function during ionizing irradiation-induced oxidative stress. Project 3 will design duel functional nitroxide/mitochondrial nitric oxide synthase (NOS) inhibitors linked to novel mitochondrial dragging and time release peptides for efficient radioprotection. Project 4 takes a novel approach toward preventing mitochondrial cardiolipin oxidation, and resultant perdxidation and release of cytochrome C. Project 5 develops small molecule protectors of mitochondrial respiratory chain complex I and III from irradiation-induced oxidative damage thereby stabilizing electron transport and preserving ATP generation. Seven cores (A) transgenic animal, B) innovative medicinal chemistry: discovery and screening, C) chemical process development, D) biostatistics, E) bioinformatics and high throughput screening, F) radiobiological standardization, and G) administrative) support the 5 projects. A Pilot Project Program and Training and Education Program will recruit research chemists at the faculty and postdoctoral/graduate student level, respectively, from multiple institutions and support their entry into the field of radiobiology and specifically radiation protector/mitigator drug development. This CMCR program should lead to a new class of radioprotector/mitigator small molecules for oral or skin patch administration to large numbers of ionizing irradiation exposed personnel.